Regulation of tyrosinase trafficking and processing by presenilins: Partial loss of function by familial Alzheimer's disease mutation

Abstract

␥-secretase ͉ pigmentation ͉ melanocyte ͉ knock-out ͉ knock-in

Pigment Epithelium-derived Factor Maintains Retinal Pigment Epithelium Function by Inhibiting Vascular Endothelial Growth Factor-R2 Signaling through γ-Secretase

“…It is known to process a series of membrane receptors into signaling molecules that can thereafter translocate (35). In the RPE, it was known to take part in the trafficking and processing of tyrosinase enzymes, responsible for normal pigmentation (39). The data presented in our report provide evidence for the first time that PEDF inhibits VEGF-induced barrier breakdown of RPE cell monolayers through the activation of ␥-secretase.…”

Studies to Investigate the in Vivo Therapeutic Window of the γ-Secretase Inhibitor N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) in the CRND8 Mouse

“…Another group has recently reported similar coat color changes in rats treated chronically with LY411,575 (Pagnozzi et al, 2004). This phenotype may be related to evidence that ␥-secretase inhibition reduces melanin synthesis, blocks melanosome pigmentation, and affects trafficking of tyrosinase (involved in the melanin synthesis pathway) (Wang et al, 2006) and that Notch is involved in cell fate determination of hair follicular stem cells (Yamamoto et al, 2003). These findings reflect a cautionary note that other side effects of chronic ␥-secretase inhibition may emerge with further testing.…”

Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

“…In addition, it is becoming increasingly clear that PS1 regulates the intracellular trafficking of several membrane proteins in neuronal and non-neuronal cells (Naruse et al, 1998;Capell et al, 2000;Annaert et al, 2001;Kim et al, 2001;Edbauer et al, 2002;Leem et al, 2002;Cai et al, 2003;Pigino et al, 2003;Wang et al, 2006). For example, expression of FAD-linked PS1 variants markedly impairs intracellular trafficking of membrane proteins in cellfree reconstitution systems (Cai et al, 2003).…”

“…For example, studies using cultured primary neurons suggest that PS1 plays a role in regulation of intracellular trafficking of selected proteins, including APP (Naruse et al, 1998;Capell et al, 2000;Kim et al, 2001;Cai et al, 2003), the neurotrophin receptor TrkB (Naruse et al, 1998), N-cadherin (Uemura et al, 2004), the PS1-interacting proteins intercellular adhesion molecule-5 (ICAM-5)/telencephalin (Annaert et al, 2001), and nicastrin (Edbauer et al, 2002;Leem et al, 2002), whereas PS2 has been shown to regulate the trafficking of cystatin C (Ghidoni et al, 2006). More recently, Wang et al (2006) have reported that, in the absence of PS1, the retinal pigment epithelium fails to undergo pigmentation because of mislocalization of 50 nm post-Golgi vesicles containing tyrosinase that would normally be transported to melanosomes. Finally, there is evidence that PS1 may play a role in the modulation of some protein kinase activities (Takashima et al, 1998;Pigino et al, 2003).…”